title: Multiple genes contribute to the virulent phenotype observed in ferrets of an H5N1 influenza virus isolated from Thailand in 2004.
abstract: Human infections with highly pathogenic H5N1 avian influenza viruses continue to occur in many parts of the world and pose a considerable public health threat. With the use of animal models, the identification of virulence determinants has been instrumental in improving our understanding of how these viruses cause severe disease in humans. Two genetically similar H5N1 viruses (A/Thailand/16/2004 and A/Thailand/SP83/2004) exhibit high or low virulence phenotypes, respectively, in multiple animal models. Reassortant viruses were generated from this virus pair and evaluated in ferrets. Each of the polymerase genes of A/Thailand/16/2004 virus individually conferred increased virulence to A/Thailand/SP83/2004 virus while the neuraminidase of the low virulence virus reduced virulence and replication efficiency of the virulent virus in ferrets unless the homologous HA was present. Our results demonstrate that H5N1 virus virulence determinants are polygenic and that there is an important correlation between polymerase adaptation, efficient replication in the host, and virulence.
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Disease, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Taronna R
authors.initials: TR
authors.lastname: Maines
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Chen
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Belser
authors.forename: Neal
authors.initials: N
authors.lastname: Van Hoeven
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Smith
authors.forename: Ruben O
authors.initials: RO
authors.lastname: Donis
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Tumpey
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Katz
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D005289:Ferrets; D015967:Gene Expression Regulation, Viral; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics* / Q000472:pathogenicity*; D007251:Influenza, Human / Q000453:epidemiology / Q000821:virology; D009976:Orthomyxoviridae Infections / Q000821:virology*; D016865:Reassortant Viruses; D013785:Thailand / Q000453:epidemiology; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000235:genetics
chemical_list: C085820:INS1 protein, influenza virus; D017361:Viral Nonstructural Proteins